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ADVATE
[Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] for
Intravenous Injection
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is a purified glycoprotein consisting of 2,332 amino acids that is synthesized by a genetically engineered CHO cell line. In culture, the CHO cell line expresses rAHF into the cell culture medium. The rAHF is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against Factor VIII is employed to selectively isolate the rAHF from the medium. The cell culture and purification processes used in the manufacture of ADVATE employ no additives of human or animal origin. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The rAHF synthesized by the CHO cells has the same biological effects on clotting as human Antihemophilic Factor [hAHF]. Structurally the recombinant protein has a similar combination of heterogeneous heavy and light chains as found in AHF (Human).
ADVATE is formulated as a sterile, non-pyrogenic, white to off-white powder for intravenous injection. When reconstituted with the provided Sterile Water for Injection, USP, the product contains the following stabilizers and excipients in targeted amounts:
Table 5 : Approximate Concentration of Stabilizer and
Excipient after Reconstitution
| Stabilizer and Excipient | 5 mL Reconstitution (for 250, 500, 1000, 1500, 2000, 3000, 4000 IU) Target | 2 mL Reconstitution (for 250, 500, 1000, 1500 IU) Target |
| Tris (hydroxymethyl) aminomethane | 10 mM | 25 mM |
| Calcium Chloride | 1.7 mM | 4.2 mM |
| Mannitol | 3.2% (w/v) | 8% (w/v) |
| Sodium Chloride | 90mM | 225 mM |
| α, α-Trehalose | 0.8% (w/v) | 2% (w/v) |
| Histidine | 10 mM | 25 mM |
| Glutathione (Reduced) | 0.08 mg/mL | 0.2 mg/mL |
| Polysorbate 80 | 0.01% (w/v) | 0.025% (w/v) |
ADVATE is available in single-dose vials that contain nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 International Units (IU) per vial. The product contains the following stabilizers and excipients: mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione. VWF is coexpressed with Factor VIII and helps to stabilize it in culture. The final product contains no more than 2 ng VWF/IU rAHF, which will not have any clinically relevant effect in patients with von Willebrand disease. The product contains no preservative.
Each vial of ADVATE is labeled with the rAHF activity expressed in International Units per vial. Biological potency is determined by an in vitro assay, which employs a Factor VIII concentrate standard that is referenced to a WHO International Standard for Factor VIII concentrates. One International Unit, as defined by the WHO standard for blood coagulation Factor VIII, human, is approximately equal to the level of Factor VIII activity found in 1 mL of fresh pooled human plasma. The specific activity of ADVATE is 4000 to 10000 International Units per milligram of protein.
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is an Antihemophilic Factor (Recombinant) indicated for control and prevention of bleeding episodes in adults and children (0-16 years) with Hemophilia A.
ADVATE is indicated in the perioperative management in adults and children (0-16 years) with Hemophilia A.
ADVATE is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children (0-16 years) with Hemophilia A.
ADVATE is not indicated for the treatment of von Willebrand disease.
For Intravenous Use After Reconstitution Only
The expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formulas:
IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 [IU/dL]/[IU/kg]
OR
Dose (International Unit) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
Examples (assuming patient's baseline Factor VIII level is < 1% of normal):
Base the dose and frequency on the individual clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to ADVATE. Although you can estimate the dose by the calculations above, whenever possible, perform appropriate laboratory tests including serial Factor VIII activity assays. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]
A guide for dosing in the treatment of bleeding episodes is provided in Table 1. The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes.
Table 1: ADVATE Dosing for Treatment of Bleeding
Episodes in Adults and Children
| Type of Bleeding Episodes | Required Peak Post-infusion Factor VIII Activity in the Blood (as % of Normal or IU/dL) | Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level |
| Minor Early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode. |
20-40 | 10-20 International Units per kga Repeat infusions every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for one to three days until the bleeding episode is resolved (as indicated by relief of pain) or healing is achieved. |
| Moderate Moderate bleeding into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma. |
30-60 | 15-30 International Units per kga Repeat infusions every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for three days or more until the bleeding episode is resolved (as indicated by relief of pain) or healing is achieved. |
| Major Significant gastrointestinal bleeding, intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath, fractures, head trauma. |
60-100 | Initial dose 30-50 International Units per kga Repeat dose 30-50 International Units per kg every 8 to 24 hours (6 to 12 hours for patients under the age of 6) until resolution of the bleeding episode has occurred. |
| a Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) | ||
A guide for dosing in perioperative management is provided in Table 2. The careful control of dose and duration of treatment is especially important in cases of major surgery.
Table 2: ADVATE Dosing for Perioperative Management in
Adults and Children
| Type of Surgery | Required Peak Post-infusion Factor VIII Activity in the Blood (% of Normal or IU/dL) | Frequency of Infusion |
| Minor Including tooth extraction |
60-100 | A single bolus infusion (30-50 International Units/kga) beginning within one hour of the operation. Optional additional dosing every 12 to 24 hours as needed to control bleeding. For dental procedures, adjunctive therapy may be considered. |
| Major Examples include intracranial, intra-abdominal, or intrathoracic surgery, joint replacement surgery |
80-120 (pre- and post-operative) | Preoperative bolus infusion: 40-60 International Units/ kga. Verify 100% activity has been achieved prior to surgery. Maintenance bolus infusion (40-60 International Units/kga) repeat infusions every 8 to 24 hours (6 to 24 hours for patients under the age of 6), depending on the desired level of Factor VIII and state of wound healing. |
| a Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) | ||
For prevention of bleeding episodes, doses between 20 to 40 International Units of Factor VIII per kg body weight every other day (3 to 4 times weekly) may be utilized. Alternatively, an every third day dosing regimen targeted to maintain FVIII trough levels ≥ 1% may be employed. Adjust dose based on the patient's clinical response.1,2
Administer ADVATE by intravenous (IV) injection after reconstitution. Ask patients to follow the specific preparation and administration procedures provided by their physicians.
For instructions, ask patients to follow the recommendations in the FDA-approved patient labeling. [See FDA-approved patient labeling]
Perform reconstitution, product administration, and handling of the administration set and needles with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted ADVATE, in an appropriate container.
The procedures below are provided as general guidelines for the preparation and reconstitution of ADVATE. Always work on a clean surface and wash your hands before performing the following procedures:
Figure A, B, C and D
 |
ADVATE is for intravenous use after reconstitution only.
Figure E and F
 |
ADVATE with 5 mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 International Units (IU). ADVATE with 2 mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000 or 1500 IU.
Reconstitute using Sterile Water for Injection, USP (sWFI) provided in the kit.
Each vial of ADVATE is labeled with the recombinant Antihemophilic Factor (rAHF) activity expressed in International Units per vial. This potency assignment employs a Factor VIII concentrate standard that is referenced to a WHO (World Health Organization) International Standard for Factor VIII concentrates and is evaluated by appropriate methodology to ensure accuracy of the results.
ADVATE is available in single-dose vials that contain the following nominal product strengths:
| Nominal Strength | Factor VIII Potency Range | NDC (Includes 5 mL sWFI Diluent) | NDC (Includes 2 mL sWFI Diluent) |
| 250 IU | 200-400 IU per vial | 0944-2960-10 | 0944-2921-02 |
| 500 IU | 401-800 IU per vial | 0944-2961-10 | 0944-2922-02 |
| 1000 IU | 801-1200 IU per vial | 0944-2962-10 | 0944-2923-02 |
| 1500 IU | 1201-1800 IU per vial | 0944-2963-10 | 0944-2924-02 |
| 2000 IU | 1801-2400 IU per vial | 0944-2964-10 | |
| 3000 IU | 2401-3600 IU per vial | 0944-2965-10 | |
| 4000 IU | 3601-4800 IU per vial | 0944-2948-10 |
Actual Factor VIII activity in International Units is stated on the label of each ADVATE carton and vial.
ADVATE is packaged with 5 mL or 2 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless Transfer Device, one Terumo Microbore Infusion set (2 mL only), one full prescribing physician insert, and one patient insert.
ADVATE should be refrigerated (2° - 8°C [36° - 46°F]) in powder form.
ADVATE may be stored at room temperature (up to 30°C [86°F]) for a period of up to 6 months not to exceed the expiration date.
The date that ADVATE is removed from refrigeration should be noted on the carton.
Do not use beyond the expiration date printed on the vial or six months after date noted on the carton, whichever is earlier. After storage at room temperature, the product must not be returned to the refrigerator. Avoid freezing to prevent damage to the diluent vial.
REFERENCES
1. Fischer K, Collins P, Björkman S, Blanchette V, Oh M, Fritsch S, Schroth P, Spotts G, Ewenstein B. Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. Haemophilia 2011 17(3):433-8.
2. Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, Schroth P, Astermark J, Spotts G, Ewenstein B, The rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe haemophilia A. J Thromb Haemost 2009 7(3):413-20.
Baxter Healthcare Corporation, Westlake Village, CA 91362 USA. Issued July 2012
The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII.
The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
ADVATE has been evaluated in five completed studies in previously treated patients (PTPs) and one ongoing study in previously untreated patients (PUPs) with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was 370.5 (range: 1 to 1,256) days and the median number of exposure days to ADVATE per subject was 128.0 (range: 1 to 598).3
The summary of adverse reactions (ADRs) with a frequency ≥ 5% (defined as adverse events occurring within 24 hours of infusion or any event causally related occurring within study period) is shown in Table 3.
No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies.
Table 3: Summary of Adverse Reactions (ADRs)a
with a Frequency ≥ 5% in 234 Treated Subjectsb
| MedDRAc System Organ Class | MedDRA Preferred Term | Number of ADRs | Number of Subjects | Percent of Subjects |
| General disorders and administration site conditions | Pyrexia | 78 | 50 | 21 |
| Nervous system disorders | Headache | 104 | 49 | 21 |
| Respiratory, thoracic and mediastinal disorders | Cough | 75 | 44 | 19 |
| Infections and infestations | Nasopharyngitis | 61 | 40 | 17 |
| Gastrointestinal disorders | Vomiting | 35 | 27 | 12 |
| Musculoskeletal and connective tissue disorders | Arthralgia | 44 | 27 | 12 |
| Injury, poisoning and procedural complications | Limb injury | 55 | 24 | 10 |
| Infections and infestations | Upper respiratory tract infection | 24 | 20 | 9 |
| Respiratory, thoracic and mediastinal disorders | Pharyngolaryngeal pain | 23 | 20 | 9 |
| Respiratory, thoracic and mediastinal disorders | Nasal congestion | 24 | 19 | 8 |
| Gastrointestinal disorders | Diarrhea | 24 | 18 | 8 |
| Gastrointestinal disorders | Nausea | 21 | 17 | 8 |
| General disorders and administration site conditions | Pair | 19 | 17 | 8 |
| Skin and subcutaneous tissue disorders | Rash | 16 | 13 | 6 |
| Infections and infestations | Ear infection | 16 | 12 | 5 |
| Injury, poisoning and procedural complications | Procedural pain | 16 | 12 | 5 |
| Respiratory, thoracic and mediastinal disorders | Rhinorrhea | 15 | 12 | 5 |
| a ADRs are defined as all Adverse Events that
occurred (a) within 24 hours after being infused with investigational product
or (b) all Adverse Events assessed related or possibly related to
investigational product or (c) Adverse Events for which the investigator's or
sponsor's opinion of causality was missing or indeterminate. b The ADVATE clinical program included 234 treated subjects from 5 completed studies in PTPs and 1 ongoing study in PUPs as of 27 March 2006. c MedDRA version 8.1 was used. |
||||
The development of Factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with pediatric PTPs ( < 6 years of age with > 50 Factor VIII exposures) and PTPs ( ≥ 10 years of age with > 150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI 0.03 to 2.91% for the risk of any Factor VIII inhibitor development).3,4 No Factor VIII inhibitors were detected in the 53 treated pediatric PTPs.
In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment), 5 (20%) of 25 subjects who received ADVATE developed inhibitors to Factor VIII.3 Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.
Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) cell protein antibodies. Of these patients, 3 showed an upward trend in antibody titer over time and 4 showed repeated but transient elevations of antibodies. 182 treated subjects were assessed for muIgG protein antibodies. Of these, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.
The following adverse reactions have been identified during post-approval use of ADVATE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs). Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.
Table 4: Post-Marketing Experience
| Organ System [MedDRA Primary SOC] | Preferred Term |
| Immune system disorders | Anaphylactic reactiona Hypersensitivitya |
| Blood and lymphatic system disorders | Factor VIII inhibition |
| General disorders and administration site conditions | Injection site reaction Chills Fatigue/Malaise Chest discomfort/pain Less-than-expected therapeutic effect |
| a These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus. | |
There are no known drug interactions reported with ADVATE. Drug interaction studies have not been performed.
REFERENCES
3. Shapiro A, Gruppo R, Pabinger I et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther 2009 9:273-283.
Included as part of the PRECAUTIONS section.
Allergic-type hypersensitivity reactions, including anaphylaxis, are possible and have been reported with ADVATE. Symptoms have manifested as dizziness, paresthesias, rash, flushing, face swelling, urticaria, dyspnea, and pruritus. [See PATIENT INFORMATION]
ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG): maximum of 0.1 ng/IU ADVATE, and hamster proteins: maximum of 1.5 ng/IU ADVATE. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.
Carefully monitor patients treated with AHF products for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures Factor VIII inhibitor concentration. [See Monitoring Laboratory Tests]
The clinical response to ADVATE may vary. If bleeding is not controlled with the recommended dose, determine the plasma level of Factor VIII and administer a sufficient dose of ADVATE to achieve a satisfactory clinical response. If the patient's plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, suspect the presence of an inhibitor (neutralizing antibodies) and perform appropriate tests as follows:
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838.
Single doses, several-fold higher than the recommended clinical dose (related to body weight), did not demonstrate any acute or toxic effect for ADVATE in laboratory animals (mouse, rat, rabbit, and dog). Multiple dose studies were not performed with ADVATE but were performed with the related product, RECOMBINATE, and with formulation buffers of ADVATE.
No studies have been conducted with the active ingredient in ADVATE to assess its mutagenic or carcinogenic potential. The CHO cell line employed in the production of ADVATE is derived from that used in the biosynthesis of RECOMBINATE [Antihemophilic Factor (Recombinant)]. ADVATE has been shown to be comparable to RECOMBINATE with respect to its biochemical and physicochemical properties, as well as its non-clinical in vivo pharmacology.
RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations in vitro, and at doses up to ten times the expected maximal clinical dose in vivo. At that concentration, it did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei formation in bone marrow polychromatic erythrocytes. Studies in animals have not been performed to evaluate carcinogenic potential.
Animal reproduction studies have not been conducted with ADVATE. It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Prescribe ADVATE only if clinically needed.
There are no adequate and well-controlled human studies that have investigated the effects of ADVATE during labor and delivery. Prescribe ADVATE only if clinically needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ADVATE is administered to a nursing woman. Prescribe ADVATE only if clinically needed.
In comparison to adults, children present with higher Factor VIII clearance (based on per kg body weight) values and thus lower half-life and recovery of Factor VIII. This may be explained by differences in body composition and should be taken into account when dosing or following Factor VIII levels in the pediatric population.5 Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, larger or more frequent dosing based on per kg body weight may be needed in this population. [See CLINICAL PHARMACOLOGY] In the ADVATE Routine Prophylaxis Clinical Study, 3 children aged 7 to < 12 and 4 adolescents aged 12 to < 16 were included in the per-protocol analysis. The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children, adolescents, and adults. [See Clinical Studies]
Clinical studies of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Individualize dose selection for geriatric patients.
REFERENCES
5. Björkman S, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Patrone L, Ewenstein BM, Collins PW, ADVATE Clinical Program Group. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010 8(4):730-6.
No symptoms of overdose with ADVATE have been reported.
Known anaphylaxis to mouse or hamster protein or other constituents of the product.
ADVATE temporarily replaces the missing coagulation Factor VIII that is needed for effective hemostasis.
The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of Factor VIII. Treatment with ADVATE normalizes the aPTT over the effective dosing period.
A randomized, crossover pharmacokinetic study of ADVATE produced at Orth, Austria (test) and RECOMBINATE [Antihemophilic Factor (Recombinant)] (reference) was conducted in 56 non-bleeding subjects. The subjects received either of the products as an IV infusion (50 ± 5 IU/kg body weight) and there was a washout period of 72 hours to 4 weeks between the two infusions. The pharmacokinetic parameters were calculated from Factor VIII activity measurements in blood samples obtained up to 48 hours following each infusion.4 Pharmacokinetic parameters for adults for each study preparation in the per-protocol analysis are presented in Table 6.
Table 6: Pharmacokinetic Parameters for ADVATE and
RECOMBINATE (Per-Protocol Analysis, Adult Subjects Age > 16 years)
| Parameter | RECOMBINATE (n = 20)a |
ADVATE (n = 20)a |
| Mean ± SD | Mean ± SD | |
| AUCM8h (IUhrs/dL)b | 1638± 357 | 1644± 338 |
| In vivo recovery (IU/dL/IU/kg)c | 2.74 ± 0.56 | 2.57 ± 0.53 |
| Half-life (hrs) | 11.16 ± 2.50 | 12.03 ± 4.15 |
| Cmax (IU/dL) | 136 ± 29 | 128 ± 28 |
| MRT (hrs) | 14.68 ± 3.82 | 15.81 ± 5.91 |
| Vss (dL/kg) | 0.43 ± 0.10 | 0.44 ± 0.10 |
| CL (dL/hr/kg) | 0.03 ± 0.01 | 0.03 ± 0.01 |
| a 56 subjects were enrolled in the clinical
study. The per-protocol analysis included 30 patients (20 adults and 10
children). The PK parameters in the table are calculated for adult subjects
only. b Area under the plasma Factor VIII concentration x time curve from 0 to 48 hours post-infusion. c Calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement. |
||
The 90% confidence intervals for the ratios of the mean AUC(0-48h) and in vivo recovery values for the test and control products were within the pre-established limits of 0.80 and 1.25. In addition, in vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. Results of this analysis indicated no significant change in the in vivo recovery at the onset of treatment and after ≥ 75 exposure days.
See the description of the clinical study results for a discussion of the effect of long-term exposure on the pharmacokinetic properties of ADVATE. [See Clinical Studies]
In an analysis of data from 58 unique subjects with 65 surgical procedures in the perioperative management study, the target Factor VIII level was met or exceeded in all cases following a single loading dose ranging from 29 to 104 IU/kg.
Pharmacokinetic parameters calculated from interim pharmacokinetic data for 51 subjects ≤ 16 years of age (per-protocol analysis) are available for 0 neonates, 3 infants, 21 children, and 27 adolescents as shown in Table 7. The clearance of ADVATE in infants, children, older children, and adolescents was 26%, 23%, 42%, and 23% higher than adults (0.031 dL/hr/kg). The half-life of ADVATE in infants, children, older children, and adolescents was 27%, 15%, 10%, and 3% lower than adults (12.08 hours). The extent to which these differences may be clinically significant is not known.
Table 7: Pharmacokinetic Parameters (Mean ± SD) of
ADVATE by Age Group (N = 51; Intent to Treat Analysis)
| Parameters | Infants (N = 3) (1 month to < 2 yrs) | Children (N = 8) (2 to < 5 yrs) |
Older Children (N = 13) (5 to < 12 yrs) |
Adolescents (N = 27) (12 to < 16 yrs) |
| AUC (IU hr/dL) | 1385± 476 | 1545 ± 616 | 1282± 509 | 1447± 528 |
| C™ (IU/dL) | 98.0 ± 10.5 | 104.6 ± 34.5 | 111.8 ± 25.7 | 113.3 ± 21.7 |
| MRT (hrs) | 11.6 ± 3.0 | 12.8 ± 2.3 | 13.1 ± 3.5 | 15.0 ± 5.6 |
| CL (dL/hr/kg) | 0.039 ± 0.015 | 0.038 ± 0.016 | 0.044 ± 0.012 | 0.038 ± 0.012 |
| Half-life (hrs) | 8.86 ± 1.78 | 10.27 ± 1.94 | 10.89 ± 1.60 | 11.70 ± 3.72 |
| Vss (dL/kg)a | 0.43 ± 0.08 | 0.46 ± 0.12 | 0.54 ± 0.07 | 0.53 ± 0.08 |
| Recoveryb IU/dL/IU/kg | 1.96 ± 0.21 | 2.05 ± 0.62 | 2.21 ± 0.44 | 2.26 ± 0.42 |
| a Volume of distribution at steady state b Incremental recovery at Cmax calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement |
||||
In a crossover pharmacokinetic study of rAHF-PFM reconstituted in 2 mL versus 5 mL Sterile Water for Injection, USP (sWFI) in previously treated severe Hemophilia A adult and adolescent patients, the AUCs of the two formulations were comparable and the 90% confidence interval ranged from 90.4 to 102.6, indicating that the two formulations are pharmacokinetically equivalent.
The original safety and efficacy study evaluated the pharmacokinetics (double-blinded, randomized, cross-over), safety, immunogenicity, and hemostatic efficacy (open-label) of ADVATE in 111 subjects. The study was conducted with 103 Caucasian; 7 Black and 1 Asian US and European previously treated subjects (PTPs with ≥ 150 exposure days) diagnosed with moderate to severe hemophilia A (FVIII level ≤ 2% of normal), who were ≥ 10 years of age (20 were 10 to < 13, 22 were 13 to < 16, and 69 were 16 years and older). Subjects with a history of or a detectable FVIII inhibitor, portal vein hypertension (INR > 1.4), presence of splenomegaly, spider angiomata, history of esophageal hemorrhage or documented esophageal varices, hypersensitivity to RECOMBINATE rAHF, or scheduled to receive immunomodulating drug were excluded. Subjects self-administered ADVATE for routine prophylaxis and for the treatment of bleeding episodes. A global assessment of efficacy was rendered by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using an ordinal scale of excellent, good, fair, or none, based on the quality of hemostasis achieved with ADVATE produced in the Orth facility for the treatment of each new bleeding episode. A total of 510 bleeding episodes were reported, with a mean (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of these 510 episodes, 439 (86%) were rated excellent or good in their response to treatment with ADVATE, 61 (12%) were rated fair, 1 (0.2%) was rated as having no response, and for 9 (2%), the response to treatment was unknown. A total of 411 (81%) bleeding episodes were managed with a single infusion, 62 (12%) required 2 infusions, 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusions of ADVATE for satisfactory resolution. A total of 162 (32%) bleeding episodes occurred spontaneously, 228 (45%) were the result of antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.4
The rate of new bleeding episodes during the protocol-mandated 75 exposure day prophylactic regimen ( ≥ 25 IU/kg body weight 3-4 times per week) was calculated as a function of the etiology of bleeding episodes for 107 evaluable subjects (n = 274 new bleeding episodes).4 These rates are presented in Table 8.
Table 8: Rate of New Bleeding Episodes During
Prophylaxis
| Bleeding Episode Etiology | Mean (± SD) New Bleeding Episodes/Subject/Month |
| Spontaneous | 0.34 ± 0.49 |
| Post-traumatic | 0.39 ± 0.46 |
| Unknowna | 0.33 ± 0.34 |
| Overall | 0.52 ± 0.71 |
| a Etiology was indeterminate | |
The pharmacokinetic properties of ADVATE were investigated at the beginning of treatment in a multicenter study of previously treated subjects and at the end of treatment in a subset of subjects (N=13) who had completed at least 75 exposure days of treatment with ADVATE. Post-infusion levels and clearance of Factor VIII during the perioperative period were examined in an interim analysis of subjects enrolled in a surgery study. The pharmacokinetics of ADVATE was investigated in an interim analysis of a study of pediatric previously treated subjects < 6 years of age. [See Pediatric Use and CLINICAL PHARMACOLOGY]
Additional (open-label) safety and efficacy data were based on 82 subjects who continued with treatment following participation in the pivotal study. An interim analysis of efficacy from the continuation study was conducted for 27 subjects who self-administered ADVATE produced in Neuchâtel on a routine prophylactic regimen during a minimum period of 50 exposure days to ADVATE. New bleeding episodes were treated with ADVATE and the outcome of treatment was rated as excellent, good, fair, or none, based on the quality of hemostasis achieved. A total of 51 new bleeding episodes occurred in 13 of the 27 subjects being treated with ADVATE. By etiology, 53% of these bleeding events resulted from trauma and 27% occurred pontaneously; the other 20% had an undetermined etiology. The response to treatment with ADVATE for the majority (63%) of all new bleeding episodes was rated as excellent or good. 86% of the bleeding episodes resolved with only 1 infusion and an additional 6% were resolved by a second infusion.
In vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. There were no significant differences between the in vivo recoveries at the onset of treatment and the in vivo recoveries after ≥ 75 exposure days.
The study design, key inclusion and exclusion criteria, treatment, number of subjects and age range for the original perioperative management study can be found in Table 9.
Table 9: Study Design, Key Inclusion and Exclusion
Criteria, Treatment, Number of Subjects and Age Range for ADVATE Perioperative
Management Study6
| Treatment(s) | Number of Subjects | Age Range, Race |
| Perioperative Management | Interim: | Interim: |
| 1. Preoperative | 10 Procedures: | 14-64 years |
| Dental loading dose: FVIII level 60-100% of normal; | Major: 6 Minor: 4 |
Caucasian: 9 |
| Major/Minor loading dose: FVIII level 80-120% of normal | Orthopedic: 5 Dental: 0 |
Black: 1 |
| Final: | ||
| 2. Intra- and Post-Operative | Final: 59 | 7-65 years |
| *BI: as clinically indicated; | Procedures: 65 | |
| *CI: initial rate for subjects > 12y: | Major: 22 | Caucasian: 55 |
| 4 IU kg-1h-1; initial rate subjects | Minor: 35 | Black: 3 |
| 5-12y: 5 IUkg-1h-1 for; then investigator-determined | Orthopedic: 40 | Asian: 1 |
| Dental: 8 | ||
| 3. Home Replacement Therapy | 7 to |
